Tumor necrosis factors generally called as TNF (typically three types, namely TNF-α, TNF-β (LT-α), LT-β) are cytokines that are produced primarily in immune cells. TNF-α being representative thereof is produced mainly in macrophages and shows various physiological activities such as small thrombi formation and apoptosis induction, etc. Excessive production (expression) of TNF-α is known to bring on diseases such as rheumatoid arthritis and the like.
Not limited to these, physiological activities by TNF-α are deeply involved in the maintenance of homeostasis in living organisms. Thus, an increase or a suppression of TNF-α production may influence living organisms in various ways. For example, in addition to that TNF-α by itself is able to suppress insulin secretion similarly to interleukin 1 (IL-1) and interferon γ (IFNγ), it is known that a combination of these physiologically active substances is toxic to pancreatic β cells and considered to be related to β-cell apoptosis in type 1 diabetes. It has also been reported that TNF gene polymorphism linked to high production of TNF-α is involved in type 1 diabetes. TNF-α is considered to be involved also in the development of type 2 diabetes (insulin-resistant diabetes). For instance, the relationship between TNF-α expression in mast cells and insulin resistance has been discussed (Non-Patent Document 5). It has been also reported that an anti-TNF antibody injected to neutralize TNF-α can relieve insulin resistance and that in TNF receptor-deficient obese mice and TNF-deficient obese mice, levels of insulin resistance were mild, etc., suggesting that a TNF (typically TNF-α) is significantly involved in the development of insulin resistance and determining its level.
Known TNF-α-binding receptors include TNF receptor 1 (tumor necrosis factor receptor 1, or also “TNFR1” hereinafter) having a molecular weight of about 55 kDa as well as TNF receptor 2 (tumor necrosis factor receptor 2, or also “TNFR2” hereinafter) having a molecular weight of about 75 kDa (e.g. Non-Patent Document 1).
Between these, TNFR1 having a presence of a region referred to as a death domain is locally expressed in various cells constituting a living organism while TNFR2 free of a death domain is an inducible receptor with a significant expression caused by a certain stimulus being found primarily in immune cells (e.g. Non-Patent Document 2). It has been known that depending on to which of the two types of receptors TNF-α binds, the physiological activity induced by the TNF-α varies. For example, TNF-α binding to TNFR1 causes activation of caspases and induces cell apoptosis (cell death) through a signal transduction pathway involving several caspases.